BB Web Ans Focus 2010 Avances en El Tto de La Ansiedad Resistente. Lanouette

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Nicole M. Lanouette, M.D.Murray B. Stein, M.D., M.P.H.Advances in the

Management of Treatment-

Resistant Anxiety DisordersAbstract:Anxiety disorders are among the most common and disabling mental illnesses. While effective treatments

exist, many patientspossibly even 50 60%remain symptomatic despite first-line treatments. With the exception of

obsessive compulsive disorder (OCD), there are generally no universal definitions of treatment resistance and many

treatments (both pharmacologic and non-pharmacologic) have not been tested specifically in refractory cases. This arti-

cle reviews the evidence for possible medication, psychotherapy, brain stimulation, and neurosurgical approaches

including some promising novel treatmentsfor managing treatment-resistant anxiety.

Anxiety disorders are among the most common anddisabling of mental disorders, making them a seri-ous public health concern (1). Anxiety disorders areassociated with an increase in physician visits andmedical costs and with reduced productivity athome and in the workplace (2). Although manypharmacological (and nonpharmacological) treat-ments exist, the evidence suggests that these disor-ders in many patientsperhaps as many as 50%60%are resistant or refractory to first-line

treatments (3). This scenario speaks to the compel-ling need for recommendations about managingsuch patients.

There are two main challenges limiting clinicianswho aim to provide evidence-based care for treat-ment-resistant anxiety disorders. The first is a gen-eral lack of agreed-upon definitions as to what con-stitutes treatment resistance in anxiety. In broadterms, our starting point in discussing treatment-resistant anxiety will be when a patient has not re-sponded to one of two first-line treatments, for ex-ample, a serotonin-selective reuptake inhibitor

(SSRI) or cognitive behavior therapy (CBT). Thesecond challenge is that few studies have testedstrategies in treatment-refractory cases. Unless oth-erwise noted, the investigations reported here werenot tested after other treatments had failed. Giventhis lack of specific data, the majority of this articleis a review of first-line efficacy studies. Althoughnot ideal, this is the best evidence currently avail-able that holds potential utility for treatment plan-ning after first-line treatments have been unsuccess-ful. Obsessive-compulsive disorder (OCD) is theonly exception; as discussed in the section on Ob-

sessive-Compulsive Disorder, there are agreed-upon definitions of treatment resistance, and strat-egies have been tested in patients with treatment-resistant OCD. An additional limitation of theliterature present for any disorder is publicationbias; positive findings are more likely to be pub-lished than negative results.

When facing a patient who appears to have atreatment-refractory disorder, a critical first step isto ensure that the patient has received adequate

first-line treatment. For example, many patientsconsidered to have a treatment-resistant disorderhave not yet received cognitive behavior therapy(CBT), which is a valid first-line therapy, and oncethey do receive such therapy respond well to it.Unfortunately, access to good-quality CBT is lim-ited in many practice settings, although computer-ized and Web-based delivery approaches are in-creasingly being investigated to increase the reachof CBT (e.g., reference 4). Assessing adherence to

CME Disclosure

Nicole M. Lanouette, M.D., Department of Psychiatry, University of California San Diego and VASan Diego Healthcare System, San Diego, CANo relevant financial relationships to disclose.

Murray B. Stein, M.D., M.P.H., Department of Psychiatry, University of California San Diego, VASan Diego Healthcare System, and Department of Family and Preventive Medicine, University ofCalifornia San Diego, San Diego, CAConsultant: Bristol Myers Squibb

Address correspondence to Murray B. Stein, M.D., M.P.H., Professor of Psychiatry and Family &Preventive Medicine, University of California, San Diego, 9500, Gilman Drive, Mailcode 0855,La Jolla, CA 92093-0855, e-mail: [email protected].

focus.psychiatryonline.org FOCUS Fall 2010, Vol. VIII, No. 4 501

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treatment is also useful to confirm that patientshave actually received an adequate trial of ther-apy and/or medication before moving on to ther-apies with a less well-established evidence base.

Another essential step is to reevaluate a patientwith a treatment-refractory disorder diagnosti-cally to ensure that the principal diagnosis is cor-rect and to ensure that there are not additionalcomorbid disorders that would require a differ-ent treatment strategy.

We refer all readers to the up-to-date APA Prac-tice Guideline for Panic Disorder (5) and Guide-line (6) and more recent Guideline Watch (7) forposttraumatic stress disorder (PTSD), as well as the2007 Guideline for OCD (8), which are all excel-lent resources on evidence-based practice for bothinitial treatment and treatment in refractory cases.The 2008 World Federation of Societies of Biolog-ical Psychiatry guidelines for the pharmacologicaltreatment of anxiety and obsessive and post-trau-

matic stress disorders is another excellent review ofevidence-based pharmacotherapy (9). Consulta-tion with a psychiatrist experienced in treating anx-iety disorders is also recommended when one isestablishing a plan of care after first-line treatmentshave failed. At the end of each section, we include acase vignette example demonstrating possible ap-proaches. Readers should note that in this review,

we generally do not discuss mechanisms of actionsor adverse effects of these medications and advisereaders to be familiar with these before using themedication in clinical practice. In addition, review-

ing the evidence for complementary or alternativetreatments is beyond the scope of this review.

PANIC DISORDER

First-line treatment for panic disorder includesany of the following: SSRI, serotonin norepineph-rine reuptake inhibitor (SNRI) (venlafaxine is themost studied, but duloxetine has a similar mecha-nism of action), tricyclic antidepressant (TCA) (themost data are available for imipramine or clomipra-mine; TCAs often are not used as first-line treat-

ment because of their side effect profile), benzodi-azepine (not adequate monotherapy if there is aco-occurring mood disorder), or CBT (5).

If one first-line treatment has failed or been inad-equate, augmentation with or switching to anotherfirst-line therapy is recommended. As with otherdisorders, augmentation is generally preferable if apatient has had a partial response, whereas switch-ing to another agent will probably be more effica-cious if there has been no response. Examples ofaugmentation strategies include adding CBT or abenzodiazepine to an SSRI or adding an SSRI to

CBT. A common reasonable switching strategy isto cross-titrate from an SSRI that has been com-pletely ineffective to another SSRI, to an SNRI, or,less commonly, to a TCA. Only one randomizedcontrolled trial (RCT) (N46) has systematicallystudied a series of interventions in patients withpanic disorder who failed to achieve remission withinitial SSRI monotherapy (10). Simon et al. (10)noted that 21% of patients achieved remission after6 weeks of initial SSRI monotherapy. Among those

who did not achieve remission, increasing the doseof the SSRI in the next phase of the study was noteffective. In the third phase of the study, remissionrates were similarly low in both groups; CBT addedto the SSRI was comparable to clonazepam addedto the SSRI. Two open, noncontrolled studiesfound CBT to be effective after failed pharmaco-therapy (11, 12).

Although there is little evidence specifically ad-dressing the question of whether therapy is effective

after failure with an SSRI, examining the more sub-stantial data on using medication in combination

with therapy as initial treatment may be informa-tive in guiding treatment planning for the patient

with a refractory disorder. An RCT of 150 patientswith panic disorder found that the combination ofCBT and an SSRI or SSRI alone was somewhatsuperior to CBT alone at the end of treatment, butthis difference was no longer significant 6 and 12months after treatment discontinuation (13). A2006 meta-analysis of 21 RCTs of antidepressantsand psychotherapy (mostly behavior therapy or

CBT) for panic disorder concluded that in the ini-tial phase of treatment, the combination of an an-tidepressant plus psychotherapy was better than ei-ther alone. In later phases of treatment,combination therapy remained more effective thanantidepressants alone but was no better than psy-chotherapy alone (14). A recent meta-analysis ofthe three RCTs that studied combining benzodiaz-epines with psychotherapy reported that there wasinadequate evidence to draw any definitive conclu-sions, but all studies found no advantage for com-bination treatment over monotherapy (15).

MONOAMINE OXIDASE INHIBITORS

Although there is evidence supporting their usein panic disorder, given their many potential ad-verse effects, monoamine oxidase inhibitors(MAOIs) should generally be reserved for situa-tions in which several first-line treatments havefailed. Phenelzine has proven effective for what

would now be called panic disorder in one open(16) and two double-blind placebo-controlledstudies (17, 18). Most studies of MAOIs were done

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before the publication of DSM-III and thereforedid not use the panic disorder diagnosis; however,the description of symptoms is consistent withpanic disorder. Doses found effective in those stud-ies were fairly low, usually up to 45 mg/day. It ispossible that higher doses may be needed for pa-tients with treatment-resistant panic disorder, butno trials specifically address this question.

The reversible MAOIs are appealing, given thatthey do not typically require adherence to a low-tyramine diet or a 2-week washout period beforestarting. However, the studies examining moclobe-mide (which is not currently available in the UnitedStates) for panic disorder have yielded mixed re-sults: two studies showed positive results, finding itcomparable to fluoxetine (19) and clomipramine(20), whereas one showed benefit only for seriouslyill patients (21), and another found no benefit overplacebo (22). Brofaromine is a reversible MAOIthat also inhibits serotonin reuptake. It is not avail-

able for use but has been found in three RCTs to bemore effective than placebo (23) and as effective asfluvoxamine (24) or clomipramine (25). Therehave been no published studies of selegiline forpanic disorder. None of the studies of MAOIs orreversible MAOIs were specifically conducted withtreatment-resistant patients, so it is not known howeffective they would be in patients for whom anSSRI, benzodiazepine, or CBT has failed.

OTHER ANTIDEPRESSANTS

As with MAOIs, the data on other antidepres-sants for panic disorder are limited to populations

with nontreatment-refractory disorders. The evi-dence in support of mirtazapine for panic disorderincludes three open-label studies (26 28) and onesmall (N27) double-blind trial showing that mir-tazapine was comparable in efficacy to fluoxetine(29). Although three small open trials found nefa-zodone to be potentially beneficial for panic disor-der (30 32), no RCTs have confirmed this finding,and its use is limited by the risk of liver toxicity. Inone very small (N11) single-blind trial, trazodone

was efficacious for panic disorder (33), but twolarger RCTs found it ineffective in enhancing CBT(34) and less effective than imipramine or alprazo-lam (35). There is insufficient evidence to eithersupport or refute the efficacy of bupropion in panicdisorder; it was found to be effective in one smallopen trial (36) but not in another (37).

ANTICONVULSANTS

Anticonvulsants have been investigated for panicdisorder in small studies, only two of which were

RCTs. In one RCT, gabapentin was efficacious inthe severely ill group, but there was no overall dif-ference between gabapentin and placebo (38). Val-proate was found to be effective in a very small openstudy (N13) among patients with panic disorderand mood instability who had not responded toCBT and a first-line medication (39). Two othervery small open-label studies also support the use ofvalproate for panic disorder, but these findings re-quire confirmation in larger RCTs before it can berecommended, particularly given its significant sideeffects. Positive results in two case series of tiagab-ine (40, 41), suggested it could be beneficial forpatients with treatment-refractory disorders. How-ever, a subsequent open trial (42) and an RCT (43)found no difference between tiagabine and placebo.One small (N14) controlled study found thatcarbamazepine was statistically, but not clinically,more effective than placebo (44). Positive results inone case series (N3) of vigabatrin (45) and one

(N28) open-label study of levetiracetam (46)suggested that further study of these agents in con-trolled trials is warranted.

ANTIPSYCHOTICS

No evidence supports the use of first-generationantipsychotics in panic disorder. There is only pre-liminary positive evidence for some second-gener-ation antipsychotics. Two open-label studies haveexamined olanzapine monotherapy (47) and olan-zapine augmentation after a failed SSRI trial (48)

with positive results. Risperidone augmentationappeared to be effective for panic disorder that hadnot responded to an SSRI and/or benzodiazepine ina small 8-week open-label study (N30) (49). Amore recent randomized, rater-blinded trial(N56) found risperidone monotherapy equiva-lent to paroxetine (50). An open-label study of pa-tients with refractory panic disorder or generalizedanxiety disorder (GAD) found that aripiprazoleaugmentation of an SSRI and/or benzodiazepinesignificantly reduced anxiety (51). Theonly data onziprasidone for refractory panic disorder is a small

case series with positive results (52). Given the sig-nificant risk of metabolic side effects and the lack ofconclusive evidence about their efficacy, second-generation antipsychotics cannot be widely recom-mended as second-line agents in panic disorder, butthey could have utility in severe refractory cases.

OTHER MEDICATIONS

The evidence points to buspirone monotherapybeing ineffective for panic disorder. Randomizeddouble-blind placebo-controlled trials have found

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buspirone to be comparable to placebo and less ef-fective than imipramine (N52) (53) and alprazo-lam (N92) (54). Another RCT (N60) detectedno difference between buspirone, imipramine, orplacebo groups (55), which the authors attributedin part to a strong placebo response. A small(N16) randomized study concluded that cloraz-epate was significantly more effective than buspi-rone (56). Another RCT (N91) found that bu-spirone did not enhance the efficacy of CBT forpanic attacks, although there was an initial benefitat 16 weeks for agoraphobia and generalized anxi-ety that did not persist (57). Because buspirone ismore commonly used clinically as an adjunctiveagent than as monotherapy, controlled trials inves-tigating its efficacy in conjunction with first-lineagents in refractory cases would be valuable.d-Cycloserine is a partial agonist of the N-meth-

yl-D-aspartate receptor that has been shown to en-hance extinction learning (58). A recent RCT lends

strong preliminary support for adding d-cy-closerine to exposure-based CBT for panic disorder(59). Although d-cycloserine requires further study,particularly in patients in whom first-line treat-ments have failed, it holds promise in enhancingCBT.

ANTIHYPERTENSIVES

There is little evidence on the use of antihyper-tensives for panic disorder and even less data ontheir use in treatment-resistant disorders. One

RCT of 25 patients with treatment-refractory dis-orders that showed positive results supports use ofpindolol to augment fluoxetine (60), but these datahave not been replicated.

OTHER PSYCHOTHERAPIES

There is substantial evidence to support use ofCBT, either in individual or group format, as afirst-line treatment in panic disorder (5), but thereis little evidence to guide the choice of alternativepsychotherapies in a patient in whom CBT has not

worked or in a patient who prefers another type oftherapy. A manualized psychoanalytic psychother-apy called panic-focused psychodynamic psycho-therapy was shown to be more effective than ap-plied relaxation training in an RCT of 49 patients

with panic disorder (61). Forms of psychodynamicpsychotherapy other than panic-focused psychody-namic psychotherapy have not been tested in con-trolled trials. Emotion-focused therapy, a support-ive psychotherapy, was found to be less effectivethan imipramine and CBT and comparable to pla-cebo for panic disorder (62). In general, beyond the

use of CBT, the evidence is sparse and essentiallynonexistent for treatment-resistant cases.

OTHER TREATMENTS

There have not been any controlled investiga-tions of electroconvulsive therapy (ECT) or repet-itive transcranial magnetic stimulation (rTMS) forrefractory panic disorder. Although most com-monly performed for refractory OCD, capsulot-omy, the neurosurgical technique of producing bi-lateral lesions in the anterior limb of the internalcapsule, has rarely been performed for severe treat-ment-refractory panic disorder. In their case seriesof 26 patients with refractory panic disorder(N8), GAD, or social phobia, Ruck et al. (63)reported significant 1-year and long-term reduc-tions in anxiety but also noted that seven patientshad substantial adverse side effects, most com-monly frontal lobe dysfunction. More recently,

deep brain stimulation (DBS) has been investigatedfor refractory OCD, but it has not been tested inpanic disorder. At this time, psychosurgical ap-proaches to treatment-refractory panic disordercannot be advocated based on the evidence.

CASE VIGNETTE

A 23-year-old female college student with panicdisorder with agoraphobia has been taking sertra-line at 200 mg/day (the highest tolerable dose forher) for 8 weeks. She reports a significant decrease

in the frequency and intensity of panic attacks butcontinues to avoid many activities because of fear ofattacks and continues to have difficulty fallingasleep because of fear of night-time panic attacks.

You add a low dose (0.25 mg) of clonazepam twicedaily. Her sleep improves, but she reports excessivedaytime sleepiness and feels cognitively dulled andcontinues to have problems with avoidance. In ad-dition, she expresses the desire to minimize the useof medication. You refer her for CBT, continue theSSRI at the present dose, and reduce the clonaz-epam to only one 0.25-mg dose at bedtime. After

12 weeks of CBT, there has been a further signifi-cant reduction in the number and intensity of at-tacks, and she has resumed many of the activitiesshe previously avoided. She finds she needs theclonazepam only a few nights a week. After 20

weeks, her panic disorder is in remission, she con-tinues to practice the techniques learned in CBT,and she no longer needs the clonazepam. You de-velop a treatment plan with her to continue theSSRI for another 6 months until summer break, at

which time you successfully taper her off it, withthe help of booster CBT sessions.

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GENERALIZED ANXIETY DISORDER

First-line treatment options for GAD includeSSRIs, SNRIs, benzodiazepines (not adequatemonotherapy for GAD with comorbid depression),buspirone, and CBT. As in panic disorder, if mono-therapy with one of these agents is not successful, areasonable next step is to either 1) augment the firstagent (usually chosen if there was a partial responseto the first treatment) or 2) switch to another first-line treatment (64).

Only one study has examined whether a differentfirst-line treatment for GAD is effective after a firsthas failed. Schneier et al. (63) examined whetheropen-label escitalopram was beneficial for persis-tent symptoms of generalized anxiety after at least12 sessions of CBT (65). Eight of the original 24participants entering the study had clinically signif-icant symptoms after 12 weeks of treatment. Fourof those eight subsequently completed 12 weeks of

open-label escitalopram treatment. Among thosefour, there was a statistical trend toward pre to postimprovement on the primary outcome measure.

Although these results are suggestive of a possiblebenefit, larger controlled trials are needed beforeany conclusions can be drawn about the efficacy ofSSRIs for residual symptoms after CBT. Therehave not yet been any studies addressing the ques-tion of whether CBT is effective for persistentsymptoms after SSRI or SNRI treatment. Likewise,studies are needed to examine whether SNRIs areeffective after a failed SSRI trial and vice versa.


There is a general paucity of data, including evenefficacy studies in treatment-naive patients, on useof other antidepressants for GAD. There has beenonly one double-blind placebo-controlled trial of aTCA for GAD. In their 8-week RCT (N230)comparing imipramine, trazodone, and diazepam,Rickels et al. (66) found all three medications supe-rior to placebo. Although diazepam worked mostquickly, imipramine showed comparable, and on

one measure even superior, efficacy by the studysend. That trial is also the only investigation of tra-zodone, which was also found to be slightly moreefficacious than diazepam at 8 weeks. There havebeen no RCTs of MAOIs or reversible MAOIsamong patients with GAD. One small (N24)double-blind, randomized trial found bupropion

XL comparable to escitalopram in anxiolytic effi-cacy, but there have not yet been any larger con-trolled confirmatory studies. Mirtazapine (67) andnefazodone (68) have shown promise for GAD inopen trials, but larger RCTs are needed. None of

these antidepressants have been systematicallytested in treatment-refractory GAD. Overall thescant available first-line efficacy evidence supportsimipramine and trazodone.

ANTIHYPERTENSIVES

Antihypertensives have received little study forGAD, and neither of the two published trials fo-cused on patients with treatment-refractory GAD.The one published RCT of-blockers (N49) forgeneralized anxiety found both propranolol andatenolol to be significantly more efficacious thanplacebo for patients awaiting therapy, but atenololproduced more intolerable cardiovascular side ef-fects leading to more study dropouts (69). A dou-ble-blind crossover trial of clonidine (N23) forpatients with GAD or panic disorder found that it

was it modestly superior to placebo for anxiety (70).

ANTIHISTAMINES

Two controlled trials, neither of which was intreatment-refractory cases, support the use of hy-droxyzine for GAD. In their RCT comparing hy-droxyzine, bromazepam, and placebo (N334),Llorca et al. (71) found that hydroxyzine was supe-rior to placebo and comparable to the benzodiaz-epine. Lader et al. (72) studied hydroxyzine, buspi-rone, and placebo among 244 patients with GAD.Only hydroxyzine, but not buspirone, was superiorto placebo on the primary outcome measure, the

Hamilton Anxiety Scale, but on secondary mea-sures both hydroxyzine and buspirone were supe-rior to placebo.

ANTICONVULSANTS

Pregabalin is an anticonvulsant approved fortreatment of GAD in Europe but not in the UnitedStates. It is marketed in the United States with in-dications for various types of chronic pain. Six pub-lished double-blind RCTs have established the ef-ficacy of pregabalin for GAD (7378). All of these

trials found pregabalin to be superior to placebo. Inthe four studies that also included an active com-parative agent, the efficacy of pregabalin was similarto that of a benzodiazepine (73, 74, 76) and ven-lafaxine (77). Although most of the trials wereshort-term, the one that examined continuationtreatment with pregabalin found it superior to pla-cebo in preventing recurrence of symptoms (78). Ameta-analysis of the six RCTs found that pregaba-lin was effective for both psychic and somatic anx-iety in a dose-dependent relationship that reached aplateau at 300 mg daily (79).

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The data for other anticonvulsants are less ro-bust. There have been no RCTs examining gabap-entin, levetiracetam, carbamazepine, or vigabatrinfor GAD. In the one published double-blind RCTof valproate for GAD (N80, all males), signifi-cantly more patients in the valproate group re-sponded compared with the placebo group (80),but more controlled trials are needed, particularlygiven the side effect profile of valproate. Althoughone open-label study of tiagabine compared withparoxetine was promising (81), three parallel-groupdouble-blind RCTs did not find it superior to pla-cebo (82).

Therefore, pregabalin is currently the only anti-convulsant with sufficient efficacy data to warrantconsidering its use for refractory GAD. Notably,however, none of the investigations of pregabalinfocused specifically on patients with treatment-re-fractory GAD, so it remains unknown how effica-cious pregabalin would be as an adjunct or stand-

alone treatment among patients in whom a first-line treatment has failed.

ANTIPSYCHOTICS

Of the typical antipsychotics, trifluoperazine car-ries an Food and Drug Administration indicationfor short-term treatment of nonpsychotic anxietybased on a 4-week RCT (N415) that found trif-luoperazine (26 mg daily) to be superior to pla-cebo for moderate to severe GAD (based on DSM-III criteria) (83). This evidence must be weighed,

however, against the significant risk of tardive dys-kinesia with typical antipsychotics, particularly

with longer-term use. In addition, that trial was notfocused on treatment-refractory GAD.

The evidence for atypical antipsychotics is cur-rently primarily limited to augmentation trials.However, many have been conducted in patients

who have treatment-refractory GAD. Pollack et al.(84) studied olanzapine compared with placeboadded to fluoxetine among 24 participants in anRCT who remained symptomatic after 6 weeks offluoxetine. Olanzapine augmentation led to signif-

icantly more responders, but not remitters, com-pared with placebo, but the olanzapine group alsogained significantly more weight (84). The data forrisperidone are mixed. One RCT (N40) of ris-peridone augmentation for persistent GAD symp-toms after at least 4 weeks of anxiolytic treatmentshowed a significant reduction in symptoms com-pared with placebo, but response rates were notstatistically significantly different (85). A larger(N417) RCT of adjunctive risperidone amongpatients with GAD who were symptomatic after 8

weeks of anxiolytic treatment found no overall dif-

ference between risperidone and placebo, butamong those participants with moderate to severesymptoms, risperidone did outperform placebo insymptom reduction (86). Although an open-labelstudy of quetiapine augmentation in 40 patients

with treatment-refractory GAD suggested that itcould be beneficial, an RCT (N70) of adjunctivequetiapine for patients remaining symptomatic af-ter 10 weeks of paroxetine CR monotherapy failedto find quetiapine better than placebo (87). How-ever a recent large (N873) RCT testing quetiap-ine XR monotherapy compared with paroxetine orplacebo found 150 mg daily of quetiapine XR orparoxetine to be equally efficacious in producingremission at 8 weeks, with the suggestion thatquetiapine XR might work faster (88). Althoughthe results are encouraging, it should be noted thistrial was not in patients with treatment-refractoryGAD. Two small open-label trials of aripiprazoleaugmentation for treatment-resistant GAD re-

ported a significant reduction in symptoms (51,89), but these preliminary data require confirma-tion in larger controlled investigations. Ziprasidonemonotherapy or augmentation was studied in anRCT of 62 patients with refractory GAD and wasnot found to be superior to placebo (90).

OTHER MEDICATIONS

Riluzole is a glutamate modulator used in thetreatment of patients with amyotrophic lateral scle-rosis. One small open-label trial (N18) of riluzole

for GAD found that it significantly reduced anxietysymptoms and led to a 67% response and 44%remission rate at 8 weeks (91). Larger controlledinvestigations are needed, however, particularlygiven the high cost of riluzole.d-Cycloserine has not yet been studied in human

clinical trials as therapy augmentation for GAD.Two novel agents, agomelatine (a melatonin ago-nist and serotonin 5-HT

2Cantagonist) (92) and

deramciclane (a serotonin 5-HT2A/2C

antagonist)(93) have shown promise for GAD in RCTs inpatients with nontreatment-refractory disorders.


Although CBT has the smallest average effect sizefor GAD compared with the effect sizes for otheranxiety disorders (94), it and applied relaxationtherapy have the largest evidence bases in support ofthem compared with other therapies in GAD (95).Given the smaller effect sizes and the fact that somepatients might prefer other styles of therapy, it is

worth examining the evidence for other therapies.There have not been any studies of other therapies

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after nonresponse to CBT. One RCT of 57 patientswith GAD supports short-term psychodynamicpsychotherapy (STPP) as being equally effective asCBT on the primary outcome measure (96); how-ever, for secondary outcome measures includingtrait anxiety and worry, CBT was superior. In arandomized trial (N326) of solution focusedtherapy, STPP, and long-term psychodynamic psy-chotherapy (LTPP) for long-standing (1 year)depressive or anxiety disorders, STPP was initiallysuperior to LTPP for anxiety disorders (examinedcollectively), but at the 3-year follow-up LTPPshowed better outcomes (97). It should be notedthat there was no CBT or relaxation therapy com-parison included, and the anxiety disorders werenot examined individually. An 11-participant opentrial of mindfulness meditation-based cognitivetherapy produced promising results, suggestingthat further study in controlled trials would be

worthwhile (98). Similarly, a treatment called inte-

grative therapy that incorporates CBT and inter-personal emotional processing therapy was effectivein an open study of 18 patients with GAD. Overall,the existing data most strongly support CBT orapplied relaxation.

OTHER TREATMENTS

ECT has not been tested for refractory GAD. Apreliminary open trial of rTMS, a noninvasive tech-nique, suggests that it could be a beneficial treat-ment for treatment-resistant GAD(99), but further

controlled trials are needed. There are no publishedhuman trials of DBS in GAD. In the only pub-lished case series of capsulotomy for GAD (N13patients with GAD), Ruck et al. (63) reported sig-nificant 1-year and long-term reductions in anxi-ety, but also noted that seven patients had substan-tial adverse side effects, most commonly frontallobe dysfunction. Therefore, neurosurgical tech-niques cannot be recommended, even for severetreatment-refractory GAD.

CASE VIGNETTE

A 55-year-old male veteran with GAD and majordepressive disorder and a history of alcohol abuse(in full, sustained remission) has not responded to40 mg/day of paroxetine (at which dose he is expe-riencing a lot of sedation) after 8 weeks. You switchto fluoxetine and gradually increase the dose to 60mg/day, which he tolerates well, and after 8 weeksat that dose he joins a CBT group. He reports feel-ing so anxious that he has difficulty concentratingin the group and continues to have difficulty sleep-ing at night. You add trazodone, which helps his

sleep, but he continues to have significant daytimeanxiety and low energy and motivation. You con-tinue the trazodone, but switch the fluoxetine tovenlafaxine XR 75 mg mg/day and gradually in-crease the dose to 225 mg/day. After 8 weeks at 225mg/day, he has had significant improvement in de-pressive and worry symptoms and finds he is moreable to use the CBT successfully.

POSTTRAUMATIC STRESS DISORDER

Exposure-based cognitive behavior psychothera-pies [including prolonged exposure therapy andcognitive processing therapy and eye movement de-sensitization and reprocessing (EMDR)] have a ro-bust evidence base in support of their efficacy forPTSD, and there is wide consensus that they arefirst-line treatments (6, 7). The 2004 APA PracticeGuideline for PTSD recommend SSRIs as first-linepharmacotherapy. However, since then, a 2007 In-

stitute of Medicine review (100) concluded thatthere was insufficient evidence to support the first-line use of SSRIs in PTSD because of the moderateeffect sizes (approximately 0.5) from most RCTs.In addition, the 2009 APA Guideline Watch forPTSD (7) concluded there has been a decrease inthe strength of evidence for SSRIs in the treatmentof combat-related PTSD based on mixed resultsfrom recent trials of SSRIs in that specific popula-tion. While we await evidence to resolve these ques-tions, given the relatively favorable side effect pro-file of SSRIs, as well as multiple RCTs (6, 7) and

meta-analyses (101, 102) in support of their use,SSRIs continue to be a reasonable first-line phar-macotherapy choice for many patients. Anotherfirst-line choice is an SNRI, in particular venlafax-ine, for which there are multiple RCTs supportingits efficacy in PTSD (103, 104).

Few studies have specifically looked at what to dowhen one first-line treatment has failed. Simon etal. (105) tested whether paroxetine CR added ontoprolonged exposure therapy was helpful for partic-ipants who remained symptomatic after eight indi-vidual prolonged exposure therapy sessions. They

did not find that paroxetine CR was any better thanplacebo, but this result could have been due to thefairly small sample size (N23). A randomized trialof sertraline alone versus sertraline with culturallytailored CBT among 10 Cambodian female refu-gees with PTSD who had not achieved remission

with an antidepressant found the combinationtreatment highly efficacious (106), suggesting thatadding CBT to an antidepressant is a reasonablenext step option. Although there is little evidence toguide next-step treatment choices, as with the otherdisorders, a reasonable first step after failure of one

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first-line agent is to augment with or switch to an-other first-line agent.

TRICYCLIC ANTIDEPRESSANTS

Two8-week trials support the efficacyof amitrip-tyline for PTSD. In their RCT of 46 combat veter-ans, Davidson et al. (107) found that amitriptyline

was superior to placebo but noted low overall re-mission rates (only 36% of amitriptyline and 28%of placebo groups were in remission by the end ofthe study). A head-to-head randomized compari-son of amitriptyline (75 mg/day) and fluoxetine (60mg/day) in 20 Bosnian combat veterans showedthat both produced a significant reduction in symp-toms (70% for amitriptyline and 60% for fluox-etine) (108). Two RCTs of imipramine andphenelzine found both medications to be superiorto placebo for PTSD (109, 110), although onenoted a small advantage for phenelzine over imip-

ramine (110). In contrast, desipramine was notfound to be efficacious for PTSD, although thisresult could be due to the small sample (N18)and short duration (4 weeks) of the crossover RCT(111). Notably, none of the tricyclic antidepressantstudies were performed specifically in treatment-resistant populations and most participants weremale combat veterans, limiting the potential gener-alizability of these findings.


The two RCTs of imipramine and phenelzinedescribed above provide evidence in support of theefficacy of phenelzine in PTSD (109, 110). An-other small (N13) double-blind placebo-con-trolled crossover study failed to find a differencebetween phenelzine and placebo after 4 weeks(112). Regarding the reversible MAOIs, only open-label studies suggest the efficacy of moclobemidefor PTSD (113, 114), and the RCTs of brofaro-mine yielded mixed results (115, 116).


The only RCT of mirtazapine for PTSD found iteffective on some, but not all, measures of symp-toms (117). Bupropion is not effective for PTSD asdemonstrated in two RCTs (118, 119), althoughthe primary focus of one trial was smoking cessa-tion (119). Two RCTs of nefazodone support itsuse in PTSD (120, 121), and an open-label study of19 veterans in whom three previous medication tri-als had failed (122) suggests that nefazodone mayhave a role in treatment-refractory PTSD, althoughits widespread clinical use is limited by potential

hepatotoxicity. Although widely used as an aug-menting agent for insomnia in PTSD (123, 124),trazodone has only been studied in one very small(N6) open-label trial (125) and not in any con-trolled studies.

ANTIPSYCHOTICS

First-generation antipsychotics have not been in-vestigated for PTSD in any published controlledtrials. The evidence for second-generation atypicalantipsychotics is largely limited to augmentationstudies. Risperidone augmentation has been inves-tigated in five controlled trials with mixed results.Three RCTs found that adjunctive risperidone waseffective particularly for the reexperiencing and hy-perarousal symptom clusters in combat veterans(126, 127) and in women who had experiencedchildhood abuse (128). However, the two othertrials did not find risperidone augmentation bene-

ficial for overall PTSD symptoms but did note im-provement specifically for sleep (129, 130) and psy-chosis (130). The only RCT of adjunctiveolanzapine among 19 patients with PTSD withonly minimal response after 12 weeks of SSRImonotherapy demonstrated significant improve-ment in PTSD, sleep, and depression symptoms,but it led to a 13-pound mean weight gain (131).There have been two RCTs of atypical antipsychot-ics as monotherapy for PTSD. Risperidone was ef-fective for the primary outcome, an overall measureof PTSD symptoms but not any secondary out-

comes in a trial of 20 women who had experiencedsexual assault or domestic violence (132). In a smallRCT (N15), olanzapine monotherapy was nobetter than placebo and caused significantly more

weight gain, but there was a high placebo responserate (133). There have not been any RCTs ofquetiapine, aripiprazole, or ziprasidone as augmen-tive or monotherapy for PTSD. Overall, atypicalantipsychotics appear to be a promising but imper-fect option for treatment-refractory PTSD.

ANTICONVULSANTS

Overall, there have been few studies of anticon-vulsants for PTSD, and they have yielded mixed tonegative results. There are three studies with clearlynegative results: one large multicenter RCT foundno difference between tiagabine and placebo forPTSD (134) and two RCTs in veterans found val-proate monotherapy to be ineffective (135, 136). Incontrast, a small RCT (N15) showed promisingresults for lamotrigine (137), but no larger fol-low-up studies have yet been published to confirmor refute this finding. Topiramate monotherapy

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was found to be effective in an RCT of civilianPTSD (138). However, augmentive topiramate

was not effective in a trial of chronic PTSD in com-bat veterans, possibly because of a higher dropoutrate in the topiramate group (139). Gabapentin hasonly been studied in one controlled 14-day trial(N48), which compared it to propranolol andplacebo in prevention of PTSD and found it to beineffective in that setting (140). Pregabalin, leveti-racetam, carbamazepine, tiagabine, and vigabatrinhave not been tested in controlled trials in PTSD.Preliminary open studies of augmentive pregabalin(N9) (141) and augmentive levetiracetam(N23) (142) in nonresponders or partial re-sponders to antidepressants suggest that these med-ications are worthy of further study in larger con-trolled trials of refractory PTSD.

ANTIHYPERTENSIVES

Propranolol has been studied for the preventionof PTSD in two RCTs that involved administeringit shortly after a traumatic event and then followingpatients over time, with generally negative results(140, 143). It has not been studied in chronic ortreatment-refractory PTSD. Neither other-blockers nor calcium channel blockers have beenstudied in controlled PTSD trials.

The -adrenergic antagonist prazosin has re-ceived considerable recent study specifically forPTSD nightmares and sleep disturbance in patients

with chronic, refractory PTSD. Although there was

heterogeneity in the number and types of treat-ments patients had tried, all of participants hadchronic PTSD and were already taking medicationsor were in therapy and could therefore be consid-ered to have treatment-refractory PTSD. Three se-quential trials (144 146) examining adjunctiveprazosin in PTSD (added to whatever stable treat-ment participants were already receiving) foundthat it was not only effective for reducing night-mares and increasing sleep time but also helpful inreducing overall PTSD symptoms. Raskind et al.conducted a 20-week double-blind crossover study

(N10) (145) and a follow-up larger RCT(N40) (144) of veterans with chronic PTSD andfound that prazosin was effective for reducingtrauma nightmares and improving sleep quality as

well as overall clinical status. Mean daily doses(taken at bedtime) in those studies were 9.5 and 13mg, respectively. Their third study was a random-ized placebo-controlled crossover study that exam-ined more specific sleep measures in addition toPTSD symptoms among 13 mostly female patients

with chronic PTSD from civilian trauma (146).They found that in addition to reducing PTSD

symptoms overall, prazosin (mean nightly dose 3mg) also significantly increased total sleep time,REM sleep time, and mean REM duration.

BENZODIAZEPINES

Somewhat surprisingly, only two very smallRCTs have looked at benzodiazepines for estab-lished PTSD, with generally negative results. Braunet al. (147) conducted a very small double-blindcrossover trial (N10) and found that alprazolam

was helpful only for nonspecific anxiety and inef-fective for core posttraumatic symptoms and notedthat it produced significant rebound anxiety. An-other very small (N6) randomized, single-blind(patient), placebo-controlled crossover trial foundthat clonazepam was ineffective for sleep distur-bances, particularly nightmares (148). Clearly,more work is needed to evaluate the utility of ben-zodiazepines for PTSD, particularly treatment-re-

sistant cases for which benzodiazepine augmenta-tion may be useful.

OTHER PHARMACOTHERAPY

d-Cycloserine was investigated in one small(N11 patients with chronic PTSD) double-blind, placebo-controlled, crossover trial in whichit was found to be generally comparable to placebo(149). However, this study did not include psycho-therapy, so it could not answer the question of

whether d-cycloserine could enhance response to

psychotherapy for patients with PTSD.


Exposure-based CBTs are first-line psychothera-peutic treatments for PTSD (6, 7). There have notbeen any studies testing other therapies for refrac-tory PTSD after CBT has failed; therefore, we can-not answer the most salient question of whether thefollowing therapies would work specifically intreatment-refractory PTSD. However, we reviewthe evidence for them in patients with nontreat-

ment-refractory PTSD, as it could be helpful inguiding treatment planning after first-line strategieshave failed.

EMDR therapy incorporates exposure-basedtherapy with guided eye movements, recall, andverbalization of traumatic memories. Althoughmany individual EMDR studies have been small,meta-analyses support the efficacy of EMDR forPTSD (150, 151). There have been conflicting re-sults of meta-analyses comparing the efficacy ofEMDR with that of CBT (152, 153). Given thatEMDR includes a type of exposure therapy, the

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question of whether the eye movements are an es-sential feature of EMDR has been raised (154). A1999 critical review (155) and a 2001 meta-analysis(152) found that the eye movements were neithernecessary nor sufficient for efficacy of EMDR, butthis finding is still being debated (156).

One controlled trial of psychodynamic psycho-therapy (N112) found it comparable to traumadesensitization and hypnotherapy and concludedthat all three therapies were superior to a wait-listcontrol (157, 158). A meta-analysis that includedpsychodynamic psychotherapy also supports its ef-ficacy for PTSD (158). A more recent randomizedtrial of 32 veterans with chronic PTSD comparinghypnotherapy or zolpidem added to an SSRI andsupportive therapy found hypnotherapy effective inreducing PTSD symptoms and as effective as zolpi-dem in number of hours of sleep but superior inimproving sleep quality (159).

OTHER TREATMENTS

Although ECT has not been studied in con-trolled trials of PTSD, there have been recentpromising results from studies of rTMS, particu-larly higher frequency right-sided rTMS. In theirRCT of low-frequency (1 Hz) rTMS, high-fre-quency (10 Hz) TMS, and sham rTMS for 24 pa-tients with PTSD, Cohen et al. (160) found that 10daily treatments over 2 weeks of 10-Hz rTMS ap-plied to the right dorsolateral prefrontal cortex(DLPFC) were superior to both low-frequency and

sham TMS in producing a significant reduction inPTSD symptoms. In a recent RCT, Boggio et al.(161) compared 20-Hz rTMS applied to either theright or left DLPFC with sham rTMS. Similar tothe study of Cohen et al., the treatments were ad-ministered in 10 daily sessions over 2 weeks. Theyfound that both right and left DLPFC rTMS wereeffective in reducing PTSD symptoms, but rightrTMS had a greater effect and led to additionalimprovements in mood and overall anxiety. Thesebenefits persisted at the 3-month follow-up. Osuchet al. (161) examined in a sham-controlled cross-

over study whether 20 sessions of 1 Hz rTMS ther-apy delivered over 35 sessions per week could en-hance prolonged exposure therapy among ninepatients with chronic, treatment-refractory PTSD(162). Overall, they did not find a statistically sig-nificant difference between the sham and activetreatment, but hyperarousal symptoms were moreimproved in the active group.

No neurosurgical techniques have been investi-gated for PTSD.

In summary, despite many cases of PTSD beingresistant to existing treatments, very little available

evidence exists to guide treatment decisions. Lack-ing this evidence, the available literature suggeststhat augmentation with atypical antipsychoticsmay be beneficial in some patients. Given its pre-liminary promising results, prazosin should bemore formally studied in treatment-resistant PTSDalgorithms.

CASE VIGNETTE

A 45-year-old female business executive withPTSD from a rape in college was unable to tolerateone SSRI (escitalopram) because of initial activa-tion and increase in anxiety. She has a history ofalcohol abuse in full, sustained remission, so sheasks to avoid any potentially addictive medications.

You start a more sedating SSRI (paroxetine) atnight, which she is better able to tolerate. After 4

weeks of a full dose, she reports improvement butcontinues to have poor sleep and nightmares. She

declines CBT because of schedule constraints. Youmaximize the dose of the SSRI and add prazosininitially 1 mg at bedtime for a week. You graduallyincrease the prazosin 1 mg every 12 weeks, andonce you reach 4 mg nightly, she reports a signifi-cant decrease in nightmares and improvement inher sleep. She also reports that her daytime concen-tration and irritability have improved and she feelsless on guard and is better able to tolerate remind-ers of the rape.

OBSESSIVE-COMPULSIVE DISORDER

First-line treatment for OCD includes CBT[specifically exposure and response prevention(ERP), at least 1320 weekly sessions with dailyhomework] and/or an SSRI, typically at high dosesfor at least 812 weeks (8). Clomipramine is alsohighly effective for OCD, but it is generally recom-mended that an SSRI be tried first, given the morefavorable side effect profile of SSRIs (8).

OCD is the only anxiety disorder for which thereare generally agreed-upon definitions of nonre-sponse. In OCD trials, nonresponders are typi-

cally participants whose Yale-Brown ObsessiveCompulsive Disorder Scale (Y-BOCS) score hasdecreased 25% or less from baseline or who havebeen rated less than much improved on the ClinicalGlobal Impressions-Improvement scale (163).These definitions are not, however, universallyused, and considerable heterogeneity among non-responders remains, leading experts in the field tocall for more scientifically validated measures of re-sponse (163). In addition, many patients called re-sponders remain symptomatic (8, 163).

If one first-line treatment has failed or has been

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inadequate, augmenting with or switching to an-other first-line therapy is recommended. As withother disorders, augmentation is generally prefera-ble if a patient has had a partial response, whereasswitching to another agent will probably be moreefficacious if there has been no response. Examplesof augmentation strategies include adding CBT toan SSRI or adding an SSRI to CBT. There is evi-dence, mostly open trials (164166), but also twocontrolled trials (167, 168), in support of addingCBT after inadequate response to an SSRI. Therehave not been any trials examining whether anSSRI is effective either as monotherapy or aug-menting treatment after nonresponse or a partialresponse to CBT. A common reasonable switchingstrategy is to cross-titrate from an SSRI that hasbeen completely ineffective to another SSRI, clomi-pramine, or an SNRI (8). Surprisingly, few con-trolled studies specifically addressed the question of

whether a second serotonergic antidepressant is ef-

fective after another failed. In one randomized,double-blind, crossover trial, 150 patients withOCD were randomly assigned to receive either par-oxetine or venlafaxine ER. After 12 weeks, the 43nonresponders were switched to the other agent for12 weeks. The authors found that 42% of nonre-sponders benefited from switching to the otheragent (169). Although venlafaxine ER and parox-etine were both initially comparably effective(170), in the latter part of the trial, paroxetine wassuperior to venlafaxine among nonresponders tothe previous agent (169). Interestingly, a placebo-

controlled trial of intravenous clomipramine foundit effective for patients with OCD who had notresponded to oral clomipramine (171), but theclinical use of intravenous clomipramine is limitedby the need for cardiac monitoring.


MAOIs have not been investigated for treat-ment-refractory OCD in controlled trials. Theonly published RCT of an MAOI as initial ther-apy for OCD generally found that phenelzine

was ineffective and fluoxetine was effective, al-though the subgroup with symmetry obsessionsdid respond to phenelzine (172). The reversibleMAOIs including moclobemide, brofaromine,and selegiline have not been investigated in con-trolled trials of OCD.


The other antidepressants have not been studiedspecifically for OCD that has not responded tofirst-line treatments. An initial treatment trial of 12

weeks of open-label mirtazapine followed by 8weeks of double-blind placebo-controlled discon-tinuation found it to be effective for OCD (173),but additional RCTs have not yet been conducted.

A single-blind, randomized, placebo-controlledtrial found that mirtazapine added to citalopramaccelerated treatment response, but responder ratesat the end of the trial were similar in the citalopramplus placebo and citalopram plus mirtazapinegroups (174). There have not been any RCTs ofnefazodone for OCD. A small open investigation ofbupropion did not find it effective for OCD (175).The only RCT of trazodone for OCD found that it

was ineffective for OCD (176).

ANTICONVULSANTS

There have not been any controlled trials of an-ticonvulsant monotherapy either for initial treat-ment or treatment for nonresponders. The one ran-

domized, but open-label study of gabapentin addedonto fluoxetine suggested that it could acceleratethe treatment response but did not lead to betteroutcomes at any time point after 2 weeks (177).

ANTIPSYCHOTICS

The vast majority of published RCTs of antipsy-chotics for OCD have studied adding an antipsy-chotic after insufficient response to an SSRI. Theoverall results have been mixed, with the exceptionof risperidone, for which results were generally pos-

itive. In an RCT, haloperidol added to fluvoxaminewas effective for treatment-refractory OCD, butonly among those patients with both OCD and tics(178). Randomized placebo-controlled trials ofolanzapine and quetiapine augmentation haveyielded mixed results. One RCT found that olan-zapine augmentation was efficacious (179),

whereas another found no difference comparedwith continuing monotherapy with an SSRI (180).Two RCTs with positive results support quetiapineaugmentation (181, 182), but three RCTs withnegative results did not find it effective (183185).

The two published RCTs comparing augmentiverisperidone with placebo for refractory OCD foundit efficacious (186, 187). A head-to-head, single-blind, randomized study comparing olanzapine torisperidone augmentation in SSRI nonrespondersfound that both medications were effective forOCD but found limited tolerability for both (dueto amenorrhea with risperidone and weight gain

with olanzapine) (188). Li et al. (189) studied ris-peridone and haloperidol in a double-blind place-bo-controlled crossover trial and found them to beequally efficacious, but risperidone was superior for

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depressive symptoms and was better tolerated over-all. Using these data, Bloch et al. (190) conducted ameta-analysis and concluded that atypical antipsy-chotics, particularly risperidone, could be useful foraugmentation in treatment-refractory cases ofOCD. They noted that the evidence was too mixedto conclusively either support or refute using olan-zapine and quetiapine (190). Matsunaga et al.(191) conducted a 1-year study of antipsychoticaugmentation for SSRI nonresponders (191). Inthat trial, 90 patients were initially treated with anSSRI for 12 weeks, followed by the addition ofCBT for 1 year. Patients who had less than 10%reduction in OCD symptoms after 12 weeks of theSSRI (N44) were also randomly assigned to re-ceive olanzapine, quetiapine, or risperidone aug-mentation of the SSRI for 1 year in addition toCBT. The authors noted that although the SSRInonresponders had a significant reduction in OCDsymptoms, their initial and final Y-BOCS scores

were higher than those of the SSRI responders, andthey experienced significant side effects from theantipsychotic augmentation (191). One promisingopen-label investigation of aripiprazole augmenta-tion for treatment-refractory OCD (192) suggeststhat it is worthy of further study in larger controlledtrials.

OTHER MEDICATIONS

Benzodiazepines have received surprisingly littlestudy for OCD, and there have not been any con-

trolled trials in treatment-refractory cases. Clonaz-epam has been studied as an initial therapy withmixed results. Of the monotherapy studies, onefound that it was effective (193), whereas anotherdid not (194), and the one augmentation studyfound no difference with placebo (195). Althoughone small RCT (N18) found that buspironemonotherapy was comparable to clomipramine fortreatment-naive patients (196), when studied as anadjunctive agent for refractory OCD, its efficacy

was not supported by the results of controlled trials(197199). An open-label investigation of riluzole

with positive results suggests that it could be worthyof further study (200). Lithium was not found to bean effective adjuvant treatment for refractory OCDin two small controlled trials (201, 202). One ofthose small studies also failed to find that triiodo-thyronine added onto clomipramine was helpfulfor clomipramine nonresponders (202). A small(N23) randomized, placebo-controlled crossoverstudy found that adding once-weekly morphine(30 45 mg) to SSRIs outperformed placeboamong participants in whom two to six previousSSRI trials had failed (203), but further investiga-

tions are needed. Likewise, promising results of asingle-blind case-control study of 44 patients withsevere treatment-refractory OCD suggests that me-mantine is worthy of further study (204).

Two small double-blind placebo-controlledstudies, one in chronic OCD (205), of single-dosedextroamphetamine (30 mg) found that it pro-duced a significantly greater reduction in symp-toms compared with placebo (205, 206). A morerecent 5-week double-blind study (N24) of dex-troamphetamine (30 mg/day) or caffeine (300 mg/day) added to an SSRI/SNRI after nonresponse(207) found that both agents produced significantdecreases in OCD symptoms.

Two randomized, double-blind, placebo-con-trolled trials ofd-cycloserine added to CBT foundthat it enhanced response to CBT, particularly inthe initial phases of treatment (208, 209). Neitherof these studies was conducted specifically with amedication-resistant population, so it is still not

clear whether d-cycloserine would be beneficial intreatment-refractory OCD.

ANTIHYPERTENSIVES

Pindolol augmentation was found to be effectivein one small RCT in treatment-refractory OCD(210), but it did not show benefit in augmentingthe initial response to fluvoxamine in another smallRCT in treatment-naive patients (211). The solerandomized double-blind study of clonidine in pa-tients with nontreatment-refractory OCD found

that it was ineffective (193).

ANTIHISTAMINES

The same study that found clonidine ineffectivefor OCD also found that diphenhydramine pro-duced a significant reduction in symptoms, al-though it was intended to be a nonactive compara-tor (193). However, this study was not in patients

with treatment-refractory OCD, and there havenot been any other studies of it. There have been noinvestigations of hydroxyzine in OCD.

PSYCHOTHERAPY AND OTHER PSYCHOSOCIALTREATMENTS

CBT for OCD can focus primarily on behavioraltechniques as in ERP therapy or primarily on cog-nitive techniques. ERP in a variety of different set-tings (individual, group, therapist guided, and pa-tient-controlled) has been the most extensivelystudied and consistently has demonstrated efficacyfor OCD, leading to its being a first-line treatmentfor OCD (8). No controlled trials studying other

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therapies after a failed trial of ERP have been con-ducted.

Although there have not been controlled trials,large open studies of both partial hospitalization(212, 213) and intensive residential treatment(214218), including long-term follow-up afterdischarge (212, 217), suggest these are worthy ofconsideration for severe treatment-refractoryOCD.

OTHER TREATMENTS

Various ablative neurosurgical techniques, in-cluding anterior capsulotomy, gamma-knife radio-surgery, and cingulotomy, have been tried for se-vere treatment-refractory OCD, but only in casereports and uncontrolled studies (219224).Therefore, it is difficult to interpret the reportedresponse rates of up to 50%. In addition, the po-tential adverse effects, including psychosis, seizures,

personality change, hydrocephalus, and executivedysfunction, indicate that ablative neurosurgeryshould be reserved for only patients with severeOCD for whom multiple first- and second-lineagents have failed (8). More recently, the less-inva-sive technique of DBS (in which electrodes con-nected to a stimulator are neurosurgically placedinto the ventral anterior limb of the internal capsuleand ventral striatum) has shown promise in twosmall studies. A small (N4) study of DBS thatincluded a blinded on/off phase showed significantbenefit during the blinded treatment in one partic-

ipant and moderate benefit for another during openfollow-up (225). More recently, Goodman et al.(226) conducted a sham stimulation-controlledstudy of six patients with severe treatment-refrac-tory OCD and found that DBS led to a significantresponse in four participants after 12 months ofstimulation.

The only evidence in support of ECT in treat-ment-refractory OCD is a case series of 32 patients(227). Therefore, although the case series reportedgenerally positive results, given the risks of anesthe-sia and memory loss, there is insufficient evidence

to support the use of ECT for OCD, although itmay have utility when there are co-occurring con-ditions for which ECT is indicated, such as depres-sion (8).

Recently rTMS, a noninvasive technique, hasbeen investigated for a variety of psychiatric disor-ders including OCD. The early sham-controlledstudies of rTMS for OCD used a low frequency (1Hz) over the left dorsolateral prefrontal cortex(228, 229) or right prefrontal cortex (230); noneshowed benefit for OCD symptoms. With use ofthose three studies, a recent meta-analysis (231)

concluded that rTMS was ineffective for OCD.Consistent with those studies, a more recent sham-controlled trial of 10 sessions of high-frequency (10Hz) rTMS over the right prefrontal cortex failed tofind benefit for OCD symptoms but did note sig-nificant decreases in depression and overall anxietysymptoms (232). In contrast, two recent sham-con-trolled studies of low-frequency (1 Hz) rTMS todifferent brain regions, including the orbital frontalcortex (233) and bilateral supplementary motorarea (234), showed significant benefit for OCDsymptoms in patients with medication-resistantOCD, suggesting that larger trials of rTMS onthese brain regions are warranted.

In summary, there have been more studies donefor treatment-refractory OCD than for any otheranxiety disorder. Although further investigationsare needed, particularly for patients in whom mul-tiple first- and second-line treatments have failed,there was sufficient evidence for the authors of the

OCD APA Practice Guideline to outline a treat-ment algorithm (8).

CASE VIGNETTE

A 33-year-old unemployed man with severeOCD who you see through a public mental healthclinic had no appreciable improvement in symp-toms after 10 weeks of citalopram 60 mg/day. Youswitch to another SSRI (fluoxetine) and titrate upto his maximally tolerated dose (80 mg/day). After8 weeks, he reports a decrease in the intensity of

obsessions and a slight decrease in time spent oncompulsions but continues to have significant dis-tress. CBT for OCD is not available in your com-munity. You add low-dose risperidone augmenta-tion (initially 0.5 mg at bedtime and then increaseto 1 mg at bedtime after 1 week) and continue thehigh-dose SSRI. After another 4 weeks, he has hada significant reduction in symptoms but notenough that he has improved functionally (i.e., hestill spends many hours per day performing com-pulsions). You increase the risperidone to 1 mgb.i.d., and within 2 weeks he notices that it is easier

to distract himself from his obsessions and the timespent on compulsions has reduced enough that heis able to start searching for work.

SOCIAL PHOBIA

First-line therapy for social anxiety disorder, alsocalled social phobia, includes SSRIs, the SNRI ven-lafaxine ER, and/or CBT (9, 235). Phenelzine isalso effective for social anxiety disorder but giventhe more favorable side effect profile of SSRIs orvenlafaxine ER, it is recommended that phenelzine

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be tried second-line (9). Clonazepam also has dem-onstrated efficacy for social phobia, but only forshort-term treatment; therefore, it is typically bestused as an addition to an SSRI or SNRI, either

when starting the SSRI/SNRI to give initial symp-tom relief or in treatment-refractory cases (9).

As with the other anxiety disorders, if one first-line treatment has failed or been inadequate, aug-menting with or switching to another first-linetherapy is the recommended next step. If a patienthas had a partial response, augmentation is typicallyrecommended, whereas switching to another first-line agent will probably be more efficacious if therehas been no response. Examples of augmentationstrategies include adding CBT and/or clonazepamto an SSRI or adding an SSRI to CBT. Althoughthere is little specific data to guide switching afterSSRI nonresponse, most experts recommendswitching from a failed SSRI to another SSRI, ven-lafaxine ER, or phenelzine (9).

There are no studies on augmenting CBT withmedication or vice versa after monotherapy with ei-ther has failed. However, studies on combining med-ication and therapy for initial treatment of social anx-iety disorder have been conducted with mixed results.Recently Blanco et al. (236) reported the results oftheir RCT (N128) comparing phenelzine, cogni-tive behavior group therapy (CBGT), or their combi-nation for initial treatment of social anxiety disorder.They found that combination treatment was most ef-ficacious; in addition, phenelzine was superior to pla-cebo but CBGT was not. In contrast, an RCT

(N295) of fluoxetine, CBGT, or their combinationfound that all treatments were superior to placebo bythe end of the study, with no advantage for combina-tion therapy (237). Therefore, although there is nospecific evidence to guide second-step treatmentchoices after failure of one first-line agent, given thestrong evidence base for SSRIs, venlafaxine, phenel-zine,and CBT, switching to another of theseagents orcombining medication and CBT would be a reason-able next step. Extremely limited evidence exists on

what to do for social anxiety disorder after two first-linetreatments have failed.Therefore, in thefollowing

we review available evidence for other treatments,most of which is from nontreatment-refractory cases.

MONOAMINE OXIDASE INHIBITORS ANDTRICYCLIC ANTIDEPRESSANTS

As described above, four RCTs support of theefficacy of phenelzine as an initial treatment forsocial anxiety disorder and, therefore, it should beconsidered in patients for whom a first-line treat-ment has failed (9). Multiple double-blind trialsdemonstrate the efficacy of the reversible MAOIs

including moclobemide (238242) and brofaro-mine (243245) in nontreatment-refractory socialanxiety disorder, although brofaromine is not cur-rently available for use, and moclobemide is notcurrently approved for use in the United States. Asmall 6-week open-label study of low-dose oral sele-giline (10 mg/d) suggested that it had modest effi-cacy for social phobia (246).

There are no controlled trials of TCAs for socialanxiety disorder.


The data in support of mirtazapine are limited toone open trial with positive results (247) and oneRCT with positive results among 66 women withsocial anxiety disorder (248); neither study was inpatients with treatment-resistant disorders. Theone RCT (N105) of nefazodone found that it

was ineffective for social phobia. Bupropion and

trazodone have not been studied in controlled trialsof social anxiety disorder.

BENZODIAZEPINES

Clonazepam is the only benzodiazepine that hasbeen studied in controlled trials for the treatment ofsocial anxiety disorder. Clonazepam monotherapyhas been shown to be more efficacious than placebo(249251), including use for long-term treatment(249), and with efficacy comparable to that of CBT(252). One RCT of 28 patients with social anxiety

disorder found clonazepam added to paroxetine tobe more efficacious than paroxetine alone on some,but not all, outcome measures, although the au-thors noted that this result could be attributable toinadequate power (253). Although none of theseinvestigations were in patients with treatment-re-fractory disorders, the first-line efficacy of clonaz-epam and the different mechanisms of action ofbenzodiazepines and SSRIs/SNRIs suggest theremay be a role for adding clonazepam to an SSRI orSNRI after a partial response.

ANTICONVULSANTS

None of the investigations of anticonvulsantshave focused on patients with treatment-refractorysocial anxiety disorder. The most promising datafor anticonvulsants in patients with nontreatment-refractory disorders are RCTs in support of gabap-entin (N69) (254) and high-dose (600 mg/day)but not low-dose (150 mg/day) pregabalin(N135) (255). Although levetiracetam initiallyappeared promising in an open-label study (256), it

was subsequently found to be ineffective for social

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Table1.RCTsofnon-fi

rst-linetreatmentsteste

dforanxietydisorders

Treatment

PanicDisorder

GAD

PTSD

OCD

SocialPhobia

Tricyclicantidepressants

Imipramine

andclomipraminefirstline

Imipramine

Amitriptyline

Clomipraminefirstline

Nodata

Imipramine

Desipramine

MAOIs

Phenelzine

Nodata

Phenelzine

Phenelzine

Phenelzinefirstline

Otherantidepressants

Mirtazapine

Trazodone

Mirtazapine

Mirtazapine(a)

Mirtazapine

Trazodone

BupropionXL

Bupropion

Trazodone

Nefazodone

Nefazodone

Benzodiazepines

First-line

First-line

Insufficientdata

Clonazepam

(m)

Clonazepam

firstline

Clonazepam

(a)

Anticonvulsants

Gabapentin

Pregabalin

Tiagabine

Nodata

Gabapentin

Tiagabine

Valproate

Valproate

Pregabalin

Carbamazep

ine

Tiagabine

Lamotrigine

Levetiracetam

Topiramate(m)

Topiramate(a)

Antipsychotics

Risperidone

(m)

Trifluoperazine(

m)

Risperidone(a)

Haloperidol(a)

Olanzapine(m)

Olanzapine(a)

Risperidone(m)

Risperidone(a)

Quetiapine(m)

Risperidone(a)

Olanzapine(a)

Olanzapine(a)

Quetiapine(a)

Olanzapine(m)

Quetiapine(a)

QuetiapineXR(m)

Ziprasidone(m

,a)

Buspirone

Monotherap

y

Firstline

Insufficientdata

Monotherapy

Monotherapy

Augmentation

Augmentation

Adrenergicagents

Pindolol(a)

Propranolol

Prazosin

(fornightm

ares/sleep)

Pindolol(a)

Pindolol(a)

Clonidine

Clonidine

Atenolol(m)

Antihistamines

Nodata

Hydroxyzine

Nodata

Diphenhydramine

Nodata

Othermedications

d-Cycloserin

e

d-Cycloserine(m)

d-Cycloserine(a)

Atomoxetine

Morphine(a)

d-Cycloserine(a)

Lithium

(a)

Oxytocin(a)

Triiodothyronine(a)

Dextroamphetamine

rTMS

Nodata

uncontrolled

studyonly

rTMS

Nodata

DBS

Nodata

Nodata

Nodata

Nodata

,

RCTwithpositiveresults;,

RCTwithnegativeresults;,

RCTwithmixedresults(e.g.,b

enefitforonesubgrouponly).Thenumberofthea

bovesymbolsnexttoaparticulartreatmentindicatesthetotalnumberofRCTs

thathavebeenpublishedtestingthattreatm

entforthatdisorder.First-line:thetreatmenthasenoughevidencethatitisconsideredafirst-lineop

tion.

Nodata:therehavebeennopublishedRCTsofthistreatment.Insufficient

data:theRCTsofthistreatmentweretoosmalltodraw

conclusions.

Boldentriesindicatethat

thestudywasinpatientswithtreatment-refractorydisorders.

(a),treatmentwasstudiedasanaugmentationstrategy;(m),treat-

mentwasstudiedasamonotherapystrateg

y.

Notethatthistablesummarizesthedataon

lyfrom

publishedrandomized,

controlledtrialsoftreatmentsthatareavailableintheUnitedStates.P

leaseseethetextfordetailsofthesestudiesaswellasforasummaryofopen-

labeltrialsandstudiesoftreatmentsnotcu

rrentlyavailableintheUnitedStates.

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anxiety disorder in two RCTs (257), one of whichwas large (N217) (258). Open trials of tiagabine(259), topiramate (260), and valproic acid (261) asinitial monotherapy for social anxiety disorder sug-gest that they are worthy of further study in con-trolled trials.

ANTIPSYCHOTICS

In the one investigation of antipsychotic aug-mentation for refractory social anxiety disorder, Si-mon et al. (49) studied open-label risperidone aug-mentation (N7 participants with social anxietydisorder) of an SSRI or benzodiazepine that pa-tients had not fully responded to after 8 previous

weeks of treatment. Although the results werepromising, further study in large, controlled trials isneeded before this can be a recommended treat-ment. A small RCT (N12) found that olanzapinemonotherapy was superior to placebo in a popula-

tion with nontreatment-refractory disorders (262).Whereas an open-label study (263) suggested a rolefor quetiapine monotherapy in social anxiety disor-der, subsequent RCTs of monotherapy for general-ized social anxiety (264) and of single-dose quetia-pine before a public speaking virtual exposure (265)did not find benefit. Given the generally high sideeffect burden of these agents, further study isneeded before they become part of standard treat-ment options for treatment-resistant social anxietydisorder.

OTHER MEDICATIONS

Although buspirone appeared to have some effi-cacy in open studies as monotherapy (266) and asan SSRI augmentation (267), two RCTs failed tofind any benefit over placebo (268, 269) or anyaugmentive effect with CBT (268, 269) for socialphobia. Riluzole has not been investigated in socialanxiety disorder. One open-label trial with positiveresults in patients previously treated with antide-pressants suggests that reboxetine (270) should beinvestigated in larger RCTs for refractory social

phobia. A small RCT (N27) of atomoxetinefound that it was not effective for social anxietydisorder (271).

ANTIHYPERTENSIVES

Although -blockers may be useful for specificperformance or test anxiety (272275), they appearto be ineffective for generalized social anxiety dis-order, including treatment-refractory cases. Pindo-lol augmentation of paroxetine was not found to besuperior to placebo in a small (N14) double-

blind, placebo-controlled crossover study amongpatients who had not responded to 10 previous

weeks of paroxetine monotherapy (276). Atenololwas shown to be ineffective as initial monotherapyfor social anxiety disorder in two randomized, con-trolled trials (276278). The -adrenergic antago-nists have not been investigated for the treatment ofsocial phobia.

OTHER PHARMACOTHERAPY

Diphenhydramine and hydroxyzine have notbeen investigated for social anxiety disorder.

The two randomized, placebo-controlled trials ofd-cycloserine in social anxiety disorder found that it

was efficacious in enhancing response to CBT (ex-posure therapy) (279, 280). Although these studies

were not in patients with treatment-resistant disor-ders, they suggest that d-cycloserine is worthy ofconsideration for enhancing an exposure therapy

trial in this population. The hormone, oxytocin,was also studied in an RCT (N25) as a potentialenhancer of exposure therapy for social anxiety dis-order but was found to be ineffective (281).


CBT, particularly exposure therapy but also cog-nitive therapy, has been shown to be effective forsocial phobia and is a first-line treatment (9). Therehave not been any controlled investigations of othertherapies in patients in whom CBT has yielded a

partial or nonresponse. Other psychotherapies,however, have shown utility for social anxiety incontrolled trials and may be worthy of consider-ation if CBT has not been effective or if it is un-available. Two recent controlled trials of a comput-erized attention training found it highly effectivefor social anxiety disorder (282, 283), although an-other controlled study did not find that attentiontraining enhanced CBGT (284). One trial (N58)found that psychodynamic group therapy and clon-azepam were more effective than clonazepam alonefor social anxiety disorder (285). Mindfulness-

based stress reduction was found to be less effectivethan CBGT for generalized social anxiety disorderin a head-to-head randomized trial (286).

OTHER TREATMENTS

There are no reported trials or case series of ECT,rTMS, or DBS for social anxiety disorder. In theircase series (N26) of capsulotomy that includedfive patients with social phobia, Ruck et al. (63)reported significant 1-year and long-term reduc-tions in anxiety, but also noted that seven patients

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had substantial adverse side effects, most com-monly frontal lobe dysfunction. Given this ex-tremely limited evidence base and the substantialside effects, capsulotomy cannot be recommendedeven for the most treatment-refractory social pho-bia.

CASE VIGNETTE

A 29-year-old male graduate student with gener-alized social phobia has not responded to 12 weeksof sertraline 150 mg/day (his maximally tolerateddose). You switch to escitalopram, which, after 8

weeks at 30 mg/day, yields only slight improve-ment in his self-consciousness and no change in hisavoidance. You add CBT, which he finds very help-ful, but he continues to have great difficulty in anygroup meetings, which he needs to attend for hisprogram. You continue CBT, but, after a 2-week

washout period and careful explanation of dietary

and medication restrictions, switch the SRRI tophenelzine and gradually increase the dose to 60mg/day. He gradually improves to the point of be-ing able to more effectively use the skills learned inCBT when attending the group meetings. Afterpracticing a public speaking exposure exercise inCBT, he is able to successfully present his workduring a talk at a national meeting. His ability tointeract with colleagues in less formal situationsalso improves, and he is able to make contacts for afuture fellowship job.

SUMMARY

A paucity of data addresses the management ofpatients with treatment-resistant anxiety disorders.For most anxiety disorders, with the exception ofOCD, there are no consistent definitions of treat-ment resistance in the literature, making it difficultto judge and compare the data that do exist acrossstudies. These severe limitations notwithstanding,there is beginning to emerge both within and acrossdisorders a literature on approaches to patients withtreatment-resistant disorders. At the present time,

the data cannot be considered compelling for anyanxiety treatment-resistant indication, but clini-cians are nonetheless frequently faced with anxietytreatment resistance, and so we present the follow-ing suggested approach based on what little pub-lished evidence is available, buttressed and ex-panded upon by our own clinical experience and byother published treatment recommendation guide-lines (59).

As described in the Introduction, this approachshould be used only after thorough diagnostic as-sessment, evaluation of adequacy of prior treat-

ment, and, ideally, consultation with colleagues ex-perienced in treatment of refractory anxietydisorders. When faced with a patient with an anx-iety disorder who remains symptomatic after anadequate trial of a first-line treatment, we recom-mend either switching to (in the case of nonre-sponse) or augmenting with (in the case of partial-response) another first-line treatment. If that isineffective, we recommend successive complete tri-als of first-line agents (if any remain untried) orsecond-line agents (with augmentation if clinicallyindicated). In general, a complete medication trial

would be 8 12 weeks at the highest tolerable dose.If a medication is effective, there are scant data toguide length of maintenance treatment; using goodclinical judgment, taking into account patient pref-erence and a risk/benefit assessment on a case-by-base basis, is advised. Although there is some vari-ation by disorder, an adequate trial of CBT wouldtypically consist of at least 1220 sessions with the

patient doing daily homework. If all first-line andsecond-line treatments have been exhausted or areclinically inappropriate, Table 1 presents the evi-dence for and against possible next-step strategies.

Although large gaps remain in our knowledge ofhow best to manage treatment-refractory anxietydisorders, recent advances offer promise.

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